Everolimus exerts anticancer effects through inhibiting the interaction of matrix metalloproteinase-7 with syndecan-2 in colon cancer cells

Am J Physiol Cell Physiol. 2024 Feb 5. doi: 10.1152/ajpcell.00669.2023. Online ahead of print.ABSTRACTPrevious work showed that matrix metalloproteinase-7 (MMP-7) regulates colon cancer activities through an interaction with syndecan-2 (SDC-2) and SDC-2-derived peptide that disrupts this interaction exhibits anticancer activity in colon cancer. Here, to identify potential anticancer agents, a library of 1379 FDA-approved drugs that interact with the MMP-7 pro-domain were virtually screened by protein-ligand docking score analysis using the GalaxyDock3 program. Among five candidates selected based on their structures and total energy values for interacting with the MMP-7 pro-domain, the known mechanistic target of rapamycin kinase (mTOR) inhibitor, everolimus, showed the highest binding affinity and strongest ability to disrupt the interaction of the MMP-7 pro-domain with the SDC-2 extracellular domain in vitro. Everolimus treatment of the HCT116 human colon cancer cell line did not affect the mRNA expression levels of MMP-7 and SDC-2, but reduced the adhesion of cells to MMP-7 pro-domain-coated plates and the cell-surface localization of MMP-7. Thus, everolimus appears to inhibit to the interaction between MMP-7 and SDC-2. Everolimus treatment of HCT116 cells also reduced their gelatin-degradation activity and anticancer activities, including colony formation. Interestingly, cells treated with sirolimus, another mTOR inhibitor, triggered less gelatin-degradation activity, sug...
Source: Am J Physiol Cell Ph... - Category: Cytology Authors: Source Type: research